Blood pressure trajectory of inpatient stroke rehabilitation patients from the Determining Optimal Post-Stroke Exercise (DOSE) trial over the first 12 months post-stroke.

Background: High blood pressure (BP) is the primary risk factor for recurrent strokes. Despite established clinical guidelines, some stroke survivors exhibit uncontrolled BP over the first 12 months post-stroke. Furthermore, research on BP trajectories in stroke survivors admitted to inpatient rehabilitation hospitals is limited. Exercise is recommended to reduce BP after stroke. However, the effect of high repetition gait training at aerobic intensities (>40% heart rate reserve; HRR) during inpatient rehabilitation on BP is unclear. We aimed to determine the effect of an aerobic gait training intervention on BP trajectory over the first 12 months post-stroke. Methods: This is a secondary analysis of the Determining Optimal Post-Stroke Exercise (DOSE) trial. Participants with stroke admitted to inpatient rehabilitation hospitals were recruited and randomized to usual care (n = 24), DOSE1 (n = 25; >2,000 steps, 40-60% HRR for >30 min/session, 20 sessions over 4 weeks), or DOSE2 (n = 25; additional DOSE1 session/day) groups. Resting BP [systolic (SBP) and diastolic (DBP)] was measured at baseline (inpatient rehabilitation admission), post-intervention (near inpatient discharge), 6- and 12-month post-stroke. Linear mixed-effects models were used to examine the effects of group and time (weeks post-stroke) on SBP, DBP and hypertension (≥140/90 mmHg; ≥130/80 mmHg, if diabetic), controlling for age, stroke type, and baseline history of hypertension. Results: No effect of intervention group on SBP, DBP, or hypertension was observed. BP increased from baseline to 12-month post-stroke for SBP (from [mean ± standard deviation] 121.8 ± 15.0 to 131.8 ± 17.8 mmHg) and for DBP (74.4 ± 9.8 to 78.5 ± 10.1 mmHg). The proportion of hypertensive participants increased from 20.8% (n = 15/72) to 32.8% (n = 19/58). These increases in BP were statistically significant: an effect [estimation (95%CI), value of p] of time was observed on SBP [0.19 (0.12-0.26) mmHg/week, p < 0.001], DBP [0.09 (0.05-0.14) mmHg/week, p < 0.001], and hypertension [OR (95%CI): 1.03 (1.01-1.05), p = 0.010]. A baseline history of hypertension was associated with higher SBP by 13.45 (8.73-18.17) mmHg, higher DBP by 5.57 (2.02-9.12) mmHg, and 42.22 (6.60-270.08) times the odds of being hypertensive at each timepoint, compared to those without. Conclusion: Blood pressure increased after inpatient rehabilitation over the first 12 months post-stroke, especially among those with a history of hypertension. The 4-week aerobic gait training intervention did not influence this trajectory.

Does the Type of Surgical Headwear Worn in the OR Matter? A Review of Evidence and Opinions.

Proper surgical attire is essential in decreasing surgical site infections; however, the effectiveness of the different types of headwear is a controversial topic. We conducted a narrative review based on studies identified through a focused literature search to summarize and critically assess evidence and opinions on the most appropriate type of headwear for OR personnel. We included 48 articles: 17 original research studies and 31 non-peer-reviewed articles of various types. Research published before 2014 mostly supports the complete coverage of all hair, which aligns with the 2015 AORN guidelines. However, more recent literature rebuts these guidelines and emphasizes the importance of clean headwear. Although earlier studies (published before 2017) lacked scientific rigor, later studies (published after 2017) have other various limitations, including missing data on compliance, surgery-related techniques, and surgical attire other than headwear. The findings from this review highlight the importance of solid evidence-based guidelines and expert collaboration.

Higher intensity walking improves global cognition during inpatient rehabilitation: a secondary analysis of a randomized control trial.

Cognitive deficits are common poststroke. Cognitive rehabilitation is typically used to improve cognitive deficits. It is unknown whether higher doses of exercise to promote motor recovery influence cognitive outcomes. Our recent trial, Determining Optimal Post-Stroke Exercise (DOSE), shows more than double the steps and aerobic minutes can be achieved during inpatient rehabilitation versus usual care, and translates to improved long-term walking outcomes. Thus, the secondary analysis aim was to determine the effect of the DOSE protocol on cognitive outcomes over 1-year poststroke. The DOSE protocol progressively increased step number and aerobic minutes during inpatient stroke rehabilitation over 20 sessions. The Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), and Trail Making Test B were completed at baseline, post-intervention, and 6- and 12-months poststroke, administered using standardized guidelines. Using the DOSE data, we used mixed-effect spline regression to model participants' trajectories of cognitive recovery, controlling for relevant covariates. Participants (Usual Care n = 25, DOSE n = 50) were 56.7(11.7) years old, and 27(10) days post stroke. For the MoCA, there were statistically significant Group × Trajectory(p = 0.019), and Group × ΔTrajectory (p = 0.018) interactions with a substantial clinically meaningful difference, from +5.44 points/month improvement of the DOSE group compared to +1.59 points/month improvement with Usual Care during the 4-week intervention. The DSST and Trails B improved over time but were not different between groups. Taking advantage of this early difference may lend support to continued efforts to increase intensity, during and after discharge from inpatient rehabilitation, to improve cognition. Clinical trial registration: www.clinicaltrials.gov, NCT01915368.

Omicron, Long-COVID, and the Safety of Elective Surgery for Adults and Children: Joint Guidance from the Therapeutics and Guidelines Committee of the Surgical Infection Society and the Surgery Strategic Clinical Network, Alberta Health Services.

Background: Active and recent coronavirus disease 2019 (COVID-19) infections are associated with morbidity and mortality after surgery in adults. Current recommendations suggest delaying elective surgery in survivors for four to 12 weeks, depending on initial illness severity. Recently, the predominant causes of COVID-19 are the highly transmissible/less virulent Omicron variant/subvariants. Moreover, increased survivability of primary infections has engendered the long-COVID syndrome, with protean manifestations that may persist for months. Considering the more than 600,000,000 COVID-19 survivors, surgeons will likely be consulted by recovered patients seeking elective operations. Knowledge gaps of the aftermath of Omicron infections raise questions whether extant guidance for timing of surgery still applies to adults or should apply to the pediatric population. Methods: Scoping review of relevant English-language literature. Results: Most supporting data derive from early in the pandemic when the Alpha variant of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) predominated. The Omicron variant/subvariants generally cause milder infections with less organ dysfunction; many infections are asymptomatic, especially in children. Data are scant with respect to adult surgical outcomes after Omicron infection, and especially so for pediatric surgical outcomes at any stage of the pandemic. Conclusions: Numerous knowledge gaps persist with respect to the disease, the recovered pre-operative patient, the nature of the proposed procedure, and supporting data. For example, should the waiting period for all but urgent elective surgery be extended beyond 12 weeks, e.g., after serious/critical illness, or for patients with long-COVID and organ dysfunction? Conversely, can the waiting periods for asymptomatic patients or vaccinated patients be shortened? How shall children be risk-stratified, considering the distinctiveness of pediatric COVID-19 and the paucity of data? Forthcoming guidelines will hopefully answer these questions but may require ongoing modifications based on additional new data and the epidemiology of emerging strains.

Implementation of increased physical therapy intensity for improving walking after stroke: Walk 'n watch protocol for a multisite stepped-wedge cluster-randomized controlled trial.

RATIONALE: Clinical practice guidelines support structured, progressive protocols for improving walking after stroke. Yet, practice is slow to change, evidenced by the little amount of walking activity in stroke rehabilitation units. Our recent study (n = 75) found that a structured, progressive protocol integrated with typical daily physical therapy improved walking and quality-of-life measures over usual care. Research therapists progressed the intensity of exercise by using heart rate and step counters worn by the participants with stroke during therapy. To have the greatest impact, our next step is to undertake an implementation trial to change practice across stroke units where we enable the entire unit to use the protocol as part of standard of care. AIMS: What is the effect of introducing structured, progressive exercise (termed the Walk 'n Watch protocol) to the standard of care on the primary outcome of walking in adult participants with stroke over the hospital inpatient rehabilitation period? Secondary outcomes will be evaluated and include quality of life. METHODS AND SAMPLE SIZE ESTIMATES: This national, multisite clinical trial will randomize 12 sites using a stepped-wedge design where each site will be randomized to deliver Usual Care initially for 4, 8, 12, or 16 months (three sites for each duration). Then, each site will switch to the Walk 'n Watch phase for the remaining duration of a total 20-month enrolment period. Each participant will be exposed to either Usual Care or Walk 'n Watch. The trial will enroll a total of 195 participants with stroke to achieve a power of 80% with a Type I error rate of 5%, allowing for 20% dropout. Participants will be medically stable adults post-stroke and able to take five steps with a maximum physical assistance from one therapist. The Walk 'n Watch protocol focuses on completing a minimum of 30 min of weight-bearing, walking-related activities (at the physical therapists' discretion) that progressively increase in intensity informed by activity trackers measuring heart rate and step number. STUDY OUTCOME(S): The primary outcome will be the change in walking endurance, measured by the 6-Minute Walk Test, from baseline (T1) to 4 weeks (T2). This change will be compared across Usual Care and Walk 'n Watch phases using a linear mixed-effects model. Additional physical, cognitive, and quality of life outcomes will be measured at T1, T2, and 12 months post-stroke (T3) by a blinded assessor. DISCUSSION: The implementation of stepped-wedge cluster-randomized trial enables the protocol to be tested under real-world conditions, involving all clinicians on the unit. It will result in all sites and all clinicians on the unit to gain expertise in protocol delivery. Hence, a deliberate outcome of the trial is facilitating changes in best practice to improve outcomes for participants with stroke in the trial and for the many participants with stroke admitted after the trial ends.

Cardiometabolic multimorbidity and activity limitation: a cross-sectional study of adults using the Canadian Longitudinal Study on Aging data.

BACKGROUND: Cardiometabolic multimorbidity (CM) is the diagnosis of 2 or more cardiometabolic conditions. Multimorbidity and individual cardiometabolic conditions have been associated with activity limitation, a common form of disability, but few studies have investigated the association between CM and activity limitation. OBJECTIVES: To estimate the prevalence of activity limitation among Canadians with CM and to quantify the association between CM and activity limitation. METHODS: Using data from the Canadian Longitudinal Study on Aging, we conducted a cross-sectional analysis of activity limitation among Canadians aged 45-85 (n = 50,777; weighted n = 13,118,474). CM was defined as the diagnosis of 2 or more of diabetes/prediabetes, myocardial infarction, and stroke, and activity limitation was evaluated using the Older Americans Resources and Services scale. Descriptive statistics and logistic and multinomial logistic regression analyses were conducted to determine the association between CM and activity limitation. RESULTS: The estimated prevalence of activity limitation among participants living with CM was 27.4% compared with 7.5% with no cardiometabolic conditions. Activity limitation increased in prevalence and severity with the number of cardiometabolic conditions. People with CM had increased odds of activity limitation compared with those without any cardiometabolic conditions (adjusted relative risk ratio = 3.99, 95% confidence interval [3.35-4.75]), and the odds increased with each additional condition. Stroke survivors had greater odds of activity limitation than those without a history of stroke and the same number of cardiometabolic conditions. CONCLUSION: Activity limitation is common among Canadians living with CM. Odds of activity limitation increase with each additional cardiometabolic condition, especially for stroke survivors.

Cardiometabolic multimorbidity (CM) is a common pattern of multimorbidity characterized by the diagnosis of 2 or more cardiometabolic conditions, such as stroke, diabetes, and myocardial infarction. Previous research has found that individuals with stroke, diabetes, or myocardial infarction are at an increased risk of activity limitation, defined by the World Health Organization as the "difficulties an individual may have in executing activities." This study investigated the prevalence, risk, and severity of activity limitation among Canadians with CM and combinations of stroke, diabetes/prediabetes, and myocardial infarction. Using data from the Canadian Longitudinal Study on Aging, the estimated prevalence of activity limitation among those living with CM was 27.4% compared with 7.5% among individuals without any cardiometabolic conditions. Individuals living with CM also had increased odds of activity limitation compared with those with no cardiometabolic conditions. Importantly, the prevalence, severity, and risk of activity limitation increased with each additional condition, especially when the cluster of conditions included stroke, suggesting an additive effect of CM on activity limitation. Based on these findings, special efforts should be made to manage chronic disease risk in individuals with a history of stroke given the increased risk of activity limitation when combined with diabetes/prediabetes and myocardial infarction.

Step Number and Aerobic Minute Exercise Prescription and Progression in Stroke: A Roadmap.

BACKGROUND: While higher therapeutic intensity improves motor recovery after stroke, translating findings from successful studies is challenging without clear exercise intensity targets. We show in the DOSE trial1 more than double the steps and aerobic minutes within a session can be achieved compared with usual care and translates to improved long-term walking outcomes. OBJECTIVE: We modeled data from this successful higher intensity multi-site RCT to develop targets for prescribing and progressing exercise for varying levels of walking impairment after stroke. METHODS: In twenty-five individuals in inpatient rehabilitation, twenty sessions were monitored for a total of 500 one-hour physical therapy sessions. For the 500 sessions, step number and aerobic minute progression were modeled using linear mixed effects regression. Using formulas from the linear mixed effects regression, targets were calculated. RESULTS: The model for step number included session number and baseline walking speed, and for aerobic minutes, session number and age. For steps, there was an increase of 73 steps per session. With baseline walking speed, for every 0.1 m/s increase, a corresponding increase of 302 steps was predicted. For aerobic minutes, there was an increase of .56 minutes of aerobic activity (ie, 34 seconds) per session. For every year increase in age, a decrease of .39 minutes (ie, 23 seconds) was predicted. CONCLUSIONS: Using data associated with better walking outcomes, we provide step number and aerobic minute targets that future studies can cross-validate. As walking speed and age are collected at admission, these models allow for uptake of routine measurement of therapeutic intensity.Registration: www.clinicaltrials.gov; NCT01915368.

Development of priorities for a Canadian strategy to advance activity-based therapies after spinal cord injury.

STUDY DESIGN: Participatory design. OBJECTIVES: Activity-based therapies (ABT) have physical and psychosocial benefits for individuals with spinal cord injury (SCI). A Canadian ABT summit was held to: (1) identify methods used in stroke rehabilitation that may be appropriate for SCI; (2) understand the current state of ABT activities in Canada; and (3) identify priorities for ABT research and care for the next five years. SETTING: Stakeholder-engaged meeting at a tertiary rehabilitation hospital. METHODS: Thirty-nine stakeholders, including individuals with SCI, frontline clinicians, healthcare administrators, researchers, funders and health policy experts, attended. Two participants were note-takers. Priority identification occurred through input from stakeholder groups, followed by individual voting. Conventional content analysis was used to synthesize the information in the meeting notes. RESULTS: The strengths of ABT in stroke rehabilitation included clear and clinically feasible definitions, measurements and interventions, and recognized requirements for implementation (e.g. behavior change, partnerships). Knowledge gaps concerning ABT activities in Canada were identified for acute and community settings, non-traumatic populations, and the interventions, equipment and standardized measures (i.e. upper limb, activity levels) used. Five priorities for ABT across the continuum of care were identified: (1) Identify current ABT activities; (2) Create a network to facilitate dialog; (3) Track engagement in ABT activities; (4) Develop and implement best practice recommendations; and (5) Study optimal timing, methods, and dose of ABT. Working groups were formed to address priorities 1-3. CONCLUSIONS: The priorities will guide SCI research and care activities in Canada over the next five years. SPONSORSHIP: Praxis Spinal Cord Institute.

Higher Doses Improve Walking Recovery During Stroke Inpatient Rehabilitation.

BACKGROUND AND PURPOSE: We investigated the effect of higher therapeutic exercise doses on walking during inpatient rehabilitation, typically commencing 1 to 4 weeks poststroke. METHODS: This phase II, blinded-assessor, randomized controlled trial recruited from 6 Canadian inpatient rehabilitation units, between 2014 and 2018. Subjects (n=75; 25/group) were randomized into: control (usual care) physical therapy: typically, 1 hour, 5 days/week; Determining Optimal Post-Stroke Exercise (DOSE1): 1 hour, 5 days/week, more than double the intensity of Control (based on aerobic minutes and walking steps); and DOSE2: 2 hours, 5 days/week, more than quadruple the intensity of Control, each for 4 weeks duration. The primary outcome, walking endurance at completion of the 4-week intervention (post-evaluation), was compared across these groups using linear regression. Secondary outcomes at post-evaluation, and longitudinal outcomes at 6 and 12-month evaluations, were also analyzed. RESULTS: Both DOSE1 (mean change 61 m [95% CI, 9-113], P=0.02) and DOSE2 (mean change 58 m, 6-110, P=0.03) demonstrated greater walking endurance compared with Control at the post-evaluation. Significant improvements were also observed with DOSE2 in gait speed (5-m walk), and both DOSE groups in quality of life (EQ-5D-5 L) compared with Control. Longitudinal analyses revealed that improvements in walking endurance from the DOSE intervention were retained during the 1-year follow-up period over usual care. CONCLUSIONS: This study provides the first preliminary evidence that patients with stroke can improve their walking recovery and quality of life with higher doses of aerobic and stepping activity within a critical time period for neurological recovery. Furthermore, walking endurance benefits achieved from a 4-week intervention are retained over the first-year poststroke. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01915368.

Factors Influencing the Delivery of Intensive Rehabilitation in Stroke: Patient Perceptions Versus Rehabilitation Therapist Perceptions.

BACKGROUND: Despite increasing evidence regarding the benefit of intensive task-specific practice and aerobic exercise in stroke rehabilitation, implementation remains difficult. The factors influencing implementation have been explored from therapists' perspectives; however, despite an increased emphasis on patient involvement in research, patients' perceptions have not yet been investigated. OBJECTIVE: The study aimed to investigate factors influencing implementation of higher intensity activity in people with stroke and to compare this with therapists' perspectives. DESIGN: The design was a cross-sectional qualitative study. METHODS: The study used semistructured interviews with people with stroke who were part of a randomized clinical trial, the Determining Optimal post-Stroke Exercise study, which delivered a higher intensity intervention. An interview guide was developed and data analyzed using implementation frameworks. Factors emerging from interviews with people with stroke were compared and contrasted with factors perceived by rehabilitation therapists. RESULTS: Ten people with stroke were interviewed before data saturation was reached. Participants had a positive attitude regarding working hard and were satisfied with the graded exercise test, high intensity intervention, and the feedback-monitoring devices. Therapists and patients had contrasting perceptions about their beliefs regarding intensive exercise and the content of the intervention, with therapists more focused on the methods and patients more focused on the personal interactions stemming from the therapeutic relationship. CONCLUSIONS: People with stroke perceived no barriers regarding the implementation of higher intensity rehabilitation in practice and were positive towards working at more intense levels. Contrastingly, from the therapists' perspective, therapists' beliefs about quality of movement and issues around staffing and resources were perceived to be barriers. In addition, therapists and people with stroke perceived the contents of the intervention differently, highlighting the importance of involving patients and clinicians in the development and evaluation of rehabilitation interventions.

Determining optimal poststroke exercise: Study protocol for a randomized controlled trial investigating therapeutic intensity and dose on functional recovery during stroke inpatient rehabilitation.

RATIONALE: A top priority in stroke rehabilitation research is determining the appropriate exercise dose to optimize recovery. Although more intensive rehabilitation very early after stroke may be deleterious to recovery, inpatient rehabilitation, occurring after acute care, may be a more appropriate setting to assess therapeutic dose on neurological recovery. HYPOTHESIS: Individuals receiving higher intensity and dose exercise programs will yield greater improvements in walking ability over usual inpatient physical therapy care. METHODS AND DESIGN: Seventy-five individuals across seven inpatient rehabilitation sites in Canada will be randomized into one of three treatment programs, each 5 days/week, for four weeks and monitored for exertion (heart rate) and repetitions (step count). STUDY OUTCOMES: The primary outcome measure is the 6 min walk and secondary outcomes include functional independence, cognitive, and quality-of-life measures. Outcome data will be assessed at four time points. SUMMARY: This trial will contribute to our knowledge of the therapeutic intensity and dose necessary to maximize functional recovery at a very important stage of rehabilitation and neural recovery poststroke.

Delivering Intensive Rehabilitation in Stroke: Factors Influencing Implementation.

Background: The evidence base for stroke rehabilitation recommends intensive and repetitive task-specific practice, as well as aerobic exercise. However, translating these -evidence-based interventions from research into clinical practice remains a major -challenge. Objective: The objective of this study was to investigate factors influencing implementation of higher-intensity activity in stroke rehabilitation settings. Design: This qualitative study used a cross-sectional design. Methods: Semi-structured interviews were conducted with rehabilitation therapists from 4 sites across 2 Canadian provinces who had experience in delivering a higher-intensity intervention as part of a clinical trial (Determining Optimal post-Stroke Exercise [DOSE]). An interview guide was developed, and data were analyzed using implementation frameworks. Results: Fifteen therapists were interviewed before data saturation was reached. Therapists and patients generally had positive experiences regarding high-intensity interventions. However, therapists felt they would adapt the protocol to accommodate their beliefs about ensuring movement quality. The requirement for all patients to have a graded exercise test and the use of sensors (eg, heart rate monitors) gave therapists confidence to push patients harder than they normally would. Paradoxically, a system that enables routine graded exercise testing and the availability of staff and equipment contribute challenges for implementation in everyday practice. Conclusions: Even therapists involved in delivering a high-intensity intervention as part of a trial wanted to adapt it for clinical practice; therefore, it is imperative that researchers are explicit regarding key intervention components and what can be adapted to help ensure implementation fidelity. Changes in therapists' beliefs and system-level changes (staffing and resources) are likely necessary to facilitate higher-intensity rehabilitation in practice.

Consumer-Based Physical Activity Monitor as a Practical Way to Measure Walking Intensity During Inpatient Stroke Rehabilitation.

BACKGROUND AND PURPOSE: Identifying practical ways to accurately measure exercise intensity and dose in clinical environments is essential to advancing stroke rehabilitation. This is especially relevant in monitoring walking activity during inpatient rehabilitation where recovery is greatest. This study evaluated the accuracy of a readily available consumer-based physical activity monitor during daily inpatient stroke rehabilitation physical therapy sessions. METHODS: Twenty-one individuals admitted to inpatient rehabilitation were monitored for a total of 471 one-hour physical therapy sessions which consisted of walking and nonwalking therapeutic activities. Participants wore a consumer-based physical activity monitor (Fitbit One) and the gold standard for assessing step count (StepWatch Activity Monitor) during physical therapy sessions. Linear mixed modeling was used to assess the relationship of the step count of the Fitbit to the StepWatch Activity Monitor. Device accuracy is reported as the percent error of the Fitbit compared with the StepWatch Activity Monitor. RESULTS: A strong relationship (slope=0.99; 95% confidence interval, 0.97-1.01) was found between the number of steps captured by the Fitbit One and the StepWatch Activity Monitor. The Fitbit One had a mean error of 10.9% (5.3) for participants with walking velocities <0.4 m/s, 6.8% (3.0) for walking velocities between 0.4 and 0.8 m/s, and 4.4% (2.8) for walking velocities >0.8 m/s. CONCLUSIONS: This study provides preliminary evidence that the Fitbit One, when positioned on the nonparetic ankle, can accurately measure walking steps early after stroke during inpatient rehabilitation physical therapy sessions. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01915368.

Multiscale modeling in the clinic: diseases of the brain and nervous system.

Computational neuroscience is a field that traces its origins to the efforts of Hodgkin and Huxley, who pioneered quantitative analysis of electrical activity in the nervous system. While also continuing as an independent field, computational neuroscience has combined with computational systems biology, and neural multiscale modeling arose as one offshoot. This consolidation has added electrical, graphical, dynamical system, learning theory, artificial intelligence and neural network viewpoints with the microscale of cellular biology (neuronal and glial), mesoscales of vascular, immunological and neuronal networks, on up to macroscales of cognition and behavior. The complexity of linkages that produces pathophysiology in neurological, neurosurgical and psychiatric disease will require multiscale modeling to provide understanding that exceeds what is possible with statistical analysis or highly simplified models: how to bring together pharmacotherapeutics with neurostimulation, how to personalize therapies, how to combine novel therapies with neurorehabilitation, how to interlace periodic diagnostic updates with frequent reevaluation of therapy, how to understand a physical disease that manifests as a disease of the mind. Multiscale modeling will also help to extend the usefulness of animal models of human diseases in neuroscience, where the disconnects between clinical and animal phenomenology are particularly pronounced. Here we cover areas of particular interest for clinical application of these new modeling neurotechnologies, including epilepsy, traumatic brain injury, ischemic disease, neurorehabilitation, drug addiction, schizophrenia and neurostimulation.

Selective targeting and therapy of metastatic and multidrug resistant tumors using a long circulating podophyllotoxin nanoparticle.

Treatment options for metastatic and multidrug resistant (MDR) tumors are limited, and most of the chemotherapeutic drugs exhibit low efficacy against MDR cancers. An anti-tubulin agent podophyllotoxin (PPT) displays high potency against MDR tumor cells. However, due to its poor solubility and non-specificity, PPT cannot be used systemically. We have developed a self-assembling nanoparticle dosage form for PPT (named Celludo) by covalently conjugating PPT and polyethylene glycol (PEG) to acetylated carboxymethyl cellulose (CMC-Ac) via ester linkages. Celludo displayed extended blood circulation with an 18-fold prolonged half-life (t1/2), 9000-fold higher area under the curve (AUC), and 1000-fold reduced clearance compared to free PPT. Tumor delivery was 500-fold higher in the Cellduo group compared to free PPT. Against the lung metastatic model of EMT6-AR1, Celludo showed selective localization in the metastatic nodules and increased the median survival to 20 d compared to 6-8 d with docetaxel and PPT treatment. In the intraperitoneal metastatic model of human ovarian NCI-ADR/RES tumor, Celludo prolonged the median survival from 50 d to 70 d, whereas the standard therapy PEGylated liposomal doxorubicin showed no effect. No major toxicity was detected with the Celludo treatment. These results demonstrate that Celludo is effective against metastatic and MDR tumors.

Correction: Deleterious Rare Variants Reveal Risk for Loss of GABAA Receptor Function in Patients with Genetic Epilepsy and in the General Population.

[This corrects the article DOI: 10.1371/journal.pone.0162883.].

Gain-of-Function Alleles in Caenorhabditis elegans Nuclear Hormone Receptor nhr-49 Are Functionally Distinct.

Nuclear hormone receptors (NHRs) are transcription factors that regulate numerous physiological and developmental processes and represent important drug targets. NHR-49, an ortholog of Hepatocyte Nuclear Factor 4 (HNF4), has emerged as a key regulator of lipid metabolism and life span in the nematode worm Caenorhabditis elegans. However, many aspects of NHR-49 function remain poorly understood, including whether and how it regulates individual sets of target genes and whether its activity is modulated by a ligand. A recent study identified three gain-of-function (gof) missense mutations in nhr-49 (nhr-49(et7), nhr-49(et8), and nhr-49(et13), respectively). These substitutions all affect the ligand-binding domain (LBD), which is critical for ligand binding and protein interactions. Thus, these alleles provide an opportunity to test how three specific residues contribute to NHR-49 dependent gene regulation. We used computational and molecular methods to delineate how these mutations alter NHR-49 activity. We find that despite originating from a screen favoring the activation of specific NHR-49 targets, all three gof alleles cause broad upregulation of NHR-49 regulated genes. Interestingly, nhr-49(et7) and nhr-49(et8) exclusively affect nhr-49 dependent activation, whereas the nhr-49(et13) surprisingly affects both nhr-49 mediated activation and repression, implicating the affected residue as dually important. We also observed phenotypic non-equivalence of these alleles, as they unexpectedly caused a long, short, and normal life span, respectively. Mechanistically, the gof substitutions altered neither protein interactions with the repressive partner NHR-66 and the coactivator MDT-15 nor the subcellular localization or expression of NHR-49. However, in silico structural modeling revealed that NHR-49 likely interacts with small molecule ligands and that the missense mutations might alter ligand binding, providing a possible explanation for increased NHR-49 activity. In sum, our findings indicate that the three nhr-49 gof alleles are non-equivalent, and highlight the conserved V411 residue affected by et13 as critical for gene activation and repression alike.

Deleterious Rare Variants Reveal Risk for Loss of GABAA Receptor Function in Patients with Genetic Epilepsy and in the General Population.

Genetic epilepsies (GEs) account for approximately 50% of all seizure disorders, and familial forms include mutations in single GABAA receptor subunit genes (GABRs). In 144 sporadic GE cases (GECs), exome sequencing of 237 ion channel genes identified 520 GABR variants. Among these variants, 33 rare variants in 11 GABR genes were present in 24 GECs. To assess functional risk of variants in GECs, we selected 8 variants found in GABRA, 3 in GABRB, and 3 in GABRG and compared them to 18 variants found in the general population for GABRA1 (n = 9), GABRB3 (n = 7), and GABRG2 (n = 2). To identify deleterious variants and gain insight into structure-function relationships, we studied the gating properties, surface expression and structural perturbations of the 32 variants. Significant reduction of GABAA receptor function was strongly associated with variants scored as deleterious and mapped within the N-terminal and transmembrane domains. In addition, 12 out of 17 variants mapped along the ß+/α- GABA binding interface, were associated with reduction in channel gating and were predicted to cause structural rearrangements of the receptor by in silico simulations. Missense or nonsense mutations of GABRA1, GABRB3 and GABRG2 primarily impair subunit biogenesis. In contrast, GABR variants affected receptor function by impairing gating, suggesting that different mechanisms are operating in GABR epilepsy susceptibility variants and disease-causing mutations. The functional impact of single GABR variants found in individuals with sporadic GEs warrants the use of molecular diagnosis and will ultimately improve the treatment of genetic epilepsies by using a personalized approach.

"Stepping Up" Activity Poststroke: Ankle-Positioned Accelerometer Can Accurately Record Steps During Slow Walking.

BACKGROUND: As physical activity in people poststroke is low, devices that monitor and provide feedback of walking activity provide motivation to engage in exercise and may assist rehabilitation professionals in auditing walking activity. However, most feedback devices are not accurate at slow walking speeds. OBJECTIVE: This study assessed the accuracy of one accelerometer to measure walking steps of community-dwelling individuals poststroke. DESIGN: This was a cross-sectional study. METHODS: Two accelerometers were positioned on the nonparetic waist and ankle of participants (N=43), and walking steps from these devices were recorded at 7 speeds (0.3-0.9 m/s) and compared with video recordings (gold standard). RESULTS: When positioned at the waist, the accelerometer had more than 10% error at all speeds, except 0.8 and 0.9 m/s, and numerous participants recorded zero steps at 0.3 to 0.5 m/s. The device had 10% or less error when positioned at the ankle for all speeds between 0.4 and 0.9 m/s. LIMITATIONS: Some participants were unable to complete the faster walking speeds due to their walking impairments and inability to maintain the requested walking speed. CONCLUSIONS: Although not recommended by the manufacturer, positioning the accelerometer at the ankle (compared with the waist) may fill a long-standing need for a readily available device that provides accurate feedback for the altered and slow walking patterns that occur with stroke.